Journal of Medical Genetics最新文献

{"title":"Sexual dimorphism in <i>SMAD3</i> pathogenic variant-harbouring individuals.","authors":"Julie Richer, Joe Davis Velchev, Sharan Goobie, Christie A Boswell-Patterson, Ingrid M B H van de Laar, Judith M A Verhagen, Marja W Wessels, Jolien W Roos-Hesselink, Ilse Luyckx, Hussein Al-Amodi, Michael W A Chu, Anne-Marie Laberge, Bekim Sadikovic, Tugce Balci, Aline Verstraeten, Bart Loeys","doi":"10.1136/jmg-2024-110219","DOIUrl":"https://doi.org/10.1136/jmg-2024-110219","url":null,"abstract":"<p><strong>Background: </strong>Individuals harbouring <i>SMAD3</i> pathogenic variants are at risk for aneurysms/dissections throughout the arterial tree. Based on prior reports of sex differences in thoracic aortic aneurysm/dissection, we investigated the sexual dimorphism for vascular events in <i>SMAD3-</i>variant-harbouring patients.</p><p><strong>Methods: </strong>We analysed two large pedigrees comprising 84 individuals segregating pathogenic missense variants affecting the same p.Arg287 residue in <i>SMAD3</i>. We excluded individuals<40 years without vascular involvement, as they were too young to be classified. Individuals were subcategorised according to sex, the presence or absence and localisation (aneurysm/dissection with or without involvement of the aortic root/ascending aorta) of vascular lesions. We complemented our familial patient cohort with 178 <i>SMAD3</i> patients reported in the literature between 2011 and 2023.</p><p><strong>Results: </strong>In our two pedigrees, 11/30 (37%) variant-harbouring females had no vascular involvement, whereas none of the variant-harboring males (n=23) had no vascular involvement (p=0.001). While the two groups did not differ by age, males were at higher risk of vascular complications (p=0.037), there was no age difference between sexes. Of the 19 females with vascular involvement, six (32%) had vascular involvment sparing the aortic root/ascending aorta, whereas of the 23 males with vascular invovlement, only one (4%) had vascular involvement sparing the aortic root/ascending aorta (p=0.034). In the literature, we identified 116 male and 62 female additional patients. In the combined cohort of 220 patients, we demonstrated an over-representation of males (p<0.001) and non-penetrance in females for vascular pathology involving the aortic root/ascending aorta (p=0.028).</p><p><strong>Conclusions: </strong>Non-penetrance is more common in women, and normal echocardiography in at-risk females is not as reassuring for risk of vasculopathy in other locations. The higher non-penetrance in women creates an ascertainment bias and results in an over-representation of male patients in the literature.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel <i>HYLS1</i> variants associated with Joubert syndrome suggest potential genotype-phenotype correlates.","authors":"Simone Gana, Fulvio D'Abrusco, Roberta Nicotra, Chiara Ghiberti, Guido Catalano, Elisa Rognone, Anna Pichiecchio, Sabrina Signorini, Enza Maria Valente","doi":"10.1136/jmg-2024-110308","DOIUrl":"10.1136/jmg-2024-110308","url":null,"abstract":"<p><p>Joubert syndrome (JS) is an inherited neurodevelopmental ciliopathy with wide clinical and genetic heterogeneity, whose paradigmatic sign is a peculiar cerebellar and brainstem malformation known as the 'molar tooth sign'. Recessive pathogenic variants in the <i>HYLS1</i> gene are associated with hydrolethalus syndrome (HLS), a severe disorder characterised by multiple developmental defects leading to intrauterine or perinatal death. However, <i>HYLS1</i> biallelic variants were also reported in three individuals with JS.Here, we report a fourth patient with a purely neurological JS carrying two compound heterozygous missense variants in the <i>HYLS1</i> gene. Notably, while all patients with lethal HLS had both variants falling within the highly conserved HYLS-1 Box, the four patients with milder JS phenotype featured at least one variant external to this evolutionary conserved domain, suggesting a possible correlation between the mutation site and the severity of the phenotype.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"3-5"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing variant of uncertain significance (VUS) interpretation in neurogenetics: collaborative experiences from a tertiary care centre.","authors":"Kayla Horowitz, Nellie H Fotopoulos, Alana J Mistry, Justin Simo, Miranda Medeiros, Isabela D Bucco, Mia Ginsberg, Emily Dwosh, Roberta La Piana, Guy A Rouleau, Allison A Dilliott, Sali M K Farhan","doi":"10.1136/jmg-2024-110122","DOIUrl":"10.1136/jmg-2024-110122","url":null,"abstract":"<p><strong>Background: </strong>The findings of variants of uncertain significance (VUS) on a clinical genetic testing report pose a challenge for attending healthcare professionals (HCPs) in patient care. Here, we describe the outcomes of multidisciplinary VUS Rounds, implemented at a neurological disease tertiary care centre, which aid in interpreting and communicating VUS identified in our neurogenetics patient population.</p><p><strong>Methods: </strong>VUS Rounds brought together genetic counsellors, molecular geneticists and scientists to evaluate VUS against genomic and phenotypic evidence and assign an internal temperature classification of 'VUS Hot', 'True VUS' or 'VUS Cold', corresponding to potential pathogenicity. Biweekly meetings were held among the committee to deliberate variant classifications, determine additional clinical management actions and discuss nuances of VUS result communication.</p><p><strong>Results: </strong>In total, 143 VUS identified in 72 individuals with neurological disease were curated between October 2022 and December 2023. Of these, 12.6% were classified as VUS Hot, carried by 22.2% of the individuals, allowing for prioritisation of additional evaluation to determine potential pathogenicity of the variants, such as clinical follow-up or segregation analysis. In contrast, 45.4% of VUS were Cold and could be eliminated from further consideration in the carrier's care. We thoroughly evaluated the various evidence that contributed to our VUS classifications and resulting clinical actions.</p><p><strong>Conclusions: </strong>The assessment of VUS leveraging multidisciplinary collaboration allowed us to delineate required follow-up analyses for our neurology patient population. Integration of VUS Rounds into healthcare practices ensures equitable knowledge dissemination among HCPs and effective incorporation of uncertain genetic results into patient care.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"37-45"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-read sequencing for detection and subtyping of Prader-Willi and Angelman syndromes.","authors":"Vahid Akbari, Sarah Dada, Yaoqing Shen, Katherine Dixon, Duha Hejla, Andrew Galbraith, Sanaa Choufani, Rosanna Weksberg, Cornelius F Boerkoel, Laura Stewart, William T Gibson, Steven J M Jones","doi":"10.1136/jmg-2024-110115","DOIUrl":"10.1136/jmg-2024-110115","url":null,"abstract":"<p><p>Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are imprinting disorders caused by genetic or epigenetic aberrations of 15q11.2-q13. Their clinical testing is often multitiered; diagnostic testing begins with methylation-specific multiplex ligation-dependent probe amplification or methylation-sensitive PCR and then proceeds to molecular subtyping to determine the mechanism and recurrence risk. Currently, correct classification of a proband's PWS/AS subtype often requires parental samples, a costly process for families and health systems. The use of nanopore sequencing for molecular diagnosis of PWS and AS has been explored by Yamada <i>et al</i>; however, to confirm heterodisomy parental data were still required. Here, we investigate genome-wide nanopore sequencing in a larger cohort of PWS (18) and AS (6) as a singular test to detect the molecular subtype, without parental data. We accurately subtyped these cases including uniparental heterodisomy, mixed iso-/heterodisomy, type 1 and 2 deletions, microdeletion and <i>UBE3A</i> indels. One PWS case with a previously unresolved diagnosis subtyped as maternal isodisomy. This work highlights the application of long-read sequencing and other imprinted regions outside of the PWS/AS critical region to resolve the molecular diagnosis and subtyping of PWS and AS without parental data. The work also outlines an approach to generically detect heterodisomy through the interrogation of distant imprinted regions.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"32-36"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Six at Sixty. Commentary on identification of the <i>PTEN</i> gene as a major contributor to autism spectrum disorder.","authors":"Merlin G Butler","doi":"10.1136/jmg-2024-110470","DOIUrl":"10.1136/jmg-2024-110470","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"48-52"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Charis Eng: an appreciation.","authors":"William D Foulkes, Shirley V Hodgson, Eamonn R Maher, Joanne Ngeow, Willie Reardon, Richard Trembath","doi":"10.1136/jmg-2024-110513","DOIUrl":"https://doi.org/10.1136/jmg-2024-110513","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":"62 1","pages":"46-47"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and mutational signatures of <i>CRB1</i>-associated retinopathies: a multicentre study.","authors":"Mo-Ying Wang, Feng-Juan Gao, Yu-Qiao Ju, Lin-Ying Guo, Cong Duan, Qing Chang, Ting Zhang, Ge-Zhi Xu, Hui Du, Yuan Zong, Xin Huang","doi":"10.1136/jmg-2024-110289","DOIUrl":"10.1136/jmg-2024-110289","url":null,"abstract":"<p><strong>Background: </strong>To delineate the clinical and mutational signatures of patients with <i>CRB1</i>-associated retinopathies.</p><p><strong>Methods: </strong>This multicentre retrospective cohort study involved 40 patients with <i>CRB1</i> mutations and 40 age-matched and gender-matched inherited retinal diseases (IRDs). The detailed phenotyping and genotyping characteristics and genotype‒phenotype correlations of the patients were analysed.</p><p><strong>Results: </strong>The mean age of <i>CRB1</i> cohort was 27.33±14.63 years. Results showed that yellowish geographic macular degeneration (66.67%), small white or yellow dots (65.6%), hyperopia (62.5%), abnormally laminated retina (61.61%), epiretinal membrane (60.6%) and nummular pigment deposits (50%) were the most common signatures in patients with <i>CRB1</i> mutations. These clinical signatures were notably more prevalent among <i>CRB1</i> patients than among individuals in other IRD groups (p<0.001). Early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA) patients are more likely to present these signatures than retinitis pigmentosa (RP) and macular dystrophy (MD) patients. Furthermore, a significant reduction in central foveal thickness coupled with pronounced thickening of the peripheral retina was observed more distinctly in patients with EOSRD/LCA (p<0.001). The choroidal thickness was not significantly altered compared to the normal controls, but was markedly reduced in the other IRD groups (p<0.001). 55 pathogenic variants were identified, 20 of which were novel. Null mutations were associated with EOSRD/LCA patients, and missense mutations were more prevalent in MD and RP patients.</p><p><strong>Conclusions: </strong>Key clinical and mutational signatures were demonstrated in this study, providing a comprehensive update on <i>CRB1</i>-associated retinopathies that will aid in diagnosis and lay the foundation for future therapeutic studies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"6-14"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>JMG</i> in 2025.","authors":"Huw Dorkins","doi":"10.1136/jmg-2024-110548","DOIUrl":"https://doi.org/10.1136/jmg-2024-110548","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":"62 1","pages":"1"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in research on the mechanism of tsRNA action in tumours.","authors":"Yan Gao, Yanzhao Huang, Kaiyun Guo, Jun Cheng, Yuting Luo, Yi Deng, Ming Lei","doi":"10.1136/jmg-2024-110437","DOIUrl":"https://doi.org/10.1136/jmg-2024-110437","url":null,"abstract":"<p><p>tsRNA is a class of non-coding RNAs derived from mature or precursor tRNAs. In recent years, more and more studies have explored the correlation between tsRNAs and tumours. tsRNAs can affect the biological behaviours of tumour cells such as proliferation, apoptosis and metastasis by regulating gene expression, protein translation or post-transcriptional regulation. In this paper, we systematically review the production, biological function and research progress of tsRNA in tumour and discuss its prospects as biomarkers and therapeutic targets.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Authors' response to the commentary by Kivela <i>et al</i> on Hany <i>et al</i> (2024).","authors":"Alan J Mighell, Chris Inglehearn","doi":"10.1136/jmg-2024-110345","DOIUrl":"10.1136/jmg-2024-110345","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"2"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}